Olmesartan medoxomil is a prodrug that is hydrolysed to olmesartan during absorption from the gastrointestinal tract. Olmesartan is a selective AT1 type angiotensin II receptor antagonist, which is by virtue of its pharmacological properties, particularly useful in the treatment of hypertension. The chemical name for olmesartan medoxomil is 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2-(1H-tetrazol-5-yl) [1,1-biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, and is represented by the following structure (formula I).

Olmesartan medoxomil was first disclosed in U.S. Pat. No. 5,616,599. The synthetic method employed is depicted in the following reaction Scheme 1, where an imidazole derivative is condensed with a dioxolyl compound, then reacted with a substituted biphenyl methyl halide to obtain trityl olmesartan medoxomil which is then deprotected to obtain crude olmesartan medoxomil.

The '599 patent also discloses a process for preparing olmesartan medoxomil in examples 18(a) and 78. The process focuses on the coupling reaction between the imidazole derivative and the substituted biphenyl methyl halide, the condensation with the dioxolyl compound and the subsequent deprotection to isolate crude olmesartan medoxomil. Example 18(a) describes the coupling reaction which involves the use of a strong base (sodium hydride). Such strong bases are hazardous and difficult to handle on an industrial scale. The coupling reaction is conducted at a temperature of 60° C. The reaction conditions in the coupling step are such that impurities are formed which require the coupled intermediate to be isolated and purified. More specifically, the coupled intermediate is isolated as a residue which requires purification by column chromatography. The chromatographed product undergoes further isolation steps involving crystallisation in diisopropyl ether. The yield of ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methyl imidazole-5-carboxylate prepared according to example 18(a) is 238.4% w/w. In example 78(a), the product of example 18 is used to produce lithium 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}-methylimidazole-5-carboxylate. The yield of trityl olmesartan medoxomil prepared according to the process in example 78 is 97.6% w/w. The overall yield of the example 18(a) and example 78 processes is 230% w/w. The overall process is hazardous, tedious, time consuming and involves many steps, including isolation steps.
WO 2004/085428 describes a process for the preparation of olmesartan medoxomil which comprises: a) ring opening the 4,4-dimethyl-2-propyl-1-[4-{2-(triphenyl methyltetrazole-5-yl)phenyl}phenyl]methyl-4,6-dihydrofuran[3,4-d]imidazole-6-one; b) condensing the resulting 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-{2-(triphenylmethyltetrazole-5-yl)phenyl}phenyl]methylimidazole-5-carboxylic acid with 4-halomethyl-5-methyl-oxo-1,3-dioxyheterocyclopentene in the presence of alkali; followed by c) deprotection to obtain olmesartan medoxomil.
There is ample literature available on the deprotection of trityl olmesartan medoxomil and purification of olmesartan medoxomil. There are also several other processes reported in the prior art for the preparation of olmesatan medoxomil and its intermediates.
The synthesis of olmesartan described in the prior art involves multiple reaction steps, each requiring different conditions, solvents, temperature, etc. This necessitates a discontinuous process and more than one isolation step, which entail longer processing time, lower yields (as product is lost during each isolation step), increased effluent load and increased solvent usage, in comparison with a continuous process. Hence, there is a constant need to develop more efficient and economical synthetic routes suitable for industrial scale up.
The present inventors have now found a way of synthesizing trityl olmesartan medoxomil and olmesartan medoxomil which avoids the multiple isolation steps used in the previously described processes.